Methods and systems for measuring cardiac parameters

ABSTRACT

Methods and systems of the present invention provide for measurement of various cardiac parameters. Methods generally involve causing a change in volume and/or pressure in a heart chamber, measuring the change, and calculating at least one cardiac parameter based on the change. Systems typically include at least one actuator, at least one sensor, and a catheter or other device for positioning at least partially in a heart chamber. In some embodiments, the system may also include a controller, such as a computer or other processor, an external actuator, an external sensor, and/or an ECG device. Methods and systems of the invention may be used to more accurately diagnose cardiac conditions in order to make more informed treatment decisions.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the priority benefit of U.S. ProvisionalPatent Application No. 60/442441 (Attorney Docket No. 21308-000800US),filed Jan. 24, 2003, the full disclosure of which is hereby incorporatedby reference. The present application is related to U.S. patentapplication Ser. Nos.: 10/______ (Attorney Docket No. 21308-000710US);and 10/______ (Attorney Docket No. 21308-001110US); both of which arefiled concurrently with the present application, and both of which arehereby incorporated fully by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to medical devices and methods.More particularly, the present invention relates to medical devices,systems, and methods for determining cardiac performance parametersbased on data obtained from an intravascular or intracardiac catheterdevice.

Intravascular and intraluminal interventions and monitoring have becomeessential in modem cardiology and other medical fields. Of particularinterest to the present invention, a variety of intravascular andintracardiac catheters, implantable sensors, and other devices andsystems have been developed for monitoring cardiac performance.

The ability to adequately treat patients suffering from or at risk ofcardiovascular diseases can be greatly enhanced by frequent, or realtime continuous, monitoring of cardiac performance and function. Forexample, patients suffering from congestive heart failure could titratedosages of certain medications if more information were available andinformation were available more often, relating to cardiac performanceand function and how they have responded to drug treatment.Additionally, the need for surgical intervention could also be betterassessed if better cardiac performance data were available. For example,it is often difficult to distinguish compromised cardiac valvularfunction due principally to aortic stenosis or mitral regurgitation fromother heart conditions such as myocardial insufficiency that causesreduced pumping ability, especially when moth conditions co-exist.

For these reasons, it would be desirable to provide improved devices,systems, and methods for monitoring cardiac performance and functionboth in and outside of medical facilities. Such improved devices,systems, and methods should allow for measuring a variety of mechanical,biological, and chemical parameters related to cardiac performance andfunction and analyzing calculated cardiac performance values based onsuch measured performance characteristics. Preferably, the devices andapparatus will include one or more intravascular catheters which allowfor periodic or continuous collection of in situ cardiac performancedata. The systems may then calculate physiodynamic cardiac performanceparameters based on the measured internal and external performance datawhich has been collected. At least some of these objectives will be metby the inventions described hereinafter.

2. Description of the Background Art

Catheters and other intravascular and intracardiac devices for measuringvarious cardiac, physiological parameters are described in co-pendingU.S. patent application Ser. No. 10/734,490, (Attorney Docket No.21308-000510US), entitled “Method and System for Monitoring and TreatingHemodynamic Parameters,” filed on Dec. 11, 2003, and commonly assignedwith the present application, the full disclosure of which is herebyincorporated by reference. Other catheters and implantable sensorscapable of measuring various physiologic parameters in the heart and/orvasculature are described in U.S. Pat. Nos. 5,814,089; 6,328,699 B1;6,438,408 B1; U.S. Patent Publication Nos. 2001/0053882 A1; 2001/0047138A1; 2002/0077568 A1; 2002/0111560 A1; 2002/0151816 A1; 2002/0156417;2002/0169445; and PCT Publication WO 02/065894 A2. The full disclosuresof each of these patents and patent publications are incorporated hereinby reference.

BRIEF SUMMARY OF THE INVENTION

Methods and systems of the present invention provide for measurement ofvarious cardiac parameters. Methods generally involve causing a changein volume and/or pressure in a heart chamber, measuring the change, andcalculating at least one cardiac parameter based on the change. Systemstypically include a catheter or other device for positioning at leastpartially in a heart chamber and including at least one actuator and atleast one sensor. A monitoring device such as those described in U.S.patent application Ser. No. 10/734,490, which was previouslyincorporated by reference, may be used. In some embodiments, animplantable device such as those described in U.S. patent applicationSer. No. 60/442,441, which was previously incorporated by reference, mayalso be used. In some embodiments, the system may also include acontroller, such as a computer or other processor, an external actuator,an ECG device, an injector device and/or the like. Methods and systemsof the invention may be used to more accurately diagnose cardiacconditions as well as precisely establish disease severity and likelyresponse to therapeutic interventions in order to make patient specifictreatment decisions.

In one aspect of the present invention, a method for measuring a cardiacperformance parameter includes: causing a change in at least one ofvolume and pressure in a heart chamber at a selected time during a heartcycle; measuring a change in at least one characteristic of the heartchamber which occurs in response to the volume change and/or thepressure change; and calculating at least one parameter of the heartchamber based on a ratio of the measured change in the characteristic toeither the volume change or the pressure change. Similar measurements ofvarious hemodynamic parameters may be made after changes induced byalterations in heart rate, electrochemical coupling,electrophysiological timing, and peripheral vascular changes.

In some embodiments, causing the change involves introducing a volume offluid into the heart chamber during diastole. The fluid may beconstrained or unconstrained. For example, introducing the volume offluid may involve releasing the fluid within the heart chamber via oneor more apertures in a catheter positioned in the chamber. Morespecifically, introducing the volume of fluid may involve inflating anexpandable balloon coupled with a catheter positioned in the heartchamber. For example, inflating the balloon may involve inflating theballoon during systole of the heart and deflating the balloon duringdiastole of the heart immediately following the systole. Alternatively,introducing the volume of fluid involves: inflating a balloon within theheart chamber during systole; deflating the balloon during diastoleimnediately following the systole; and releasing an amount ofunconstrained fluid within the heart chamber during the diastole. Forexample, the balloon may be deflated by a volume equal to the amount ofthe released fluid. Alternatively, the balloon may be deflated by avolume greater than the amount of the released fluid. In someembodiments, causing the change comprises activating a hydrophone atleast once during diastole. The hydrophone may be activated at anysuitable frequency, but in some embodiments it is activated at afrequency of about 200 Hz. Further embodiments involve changes indiastolic filling period and post-extrasystolic potentiation relatedmeasurements, as occurs with spontaneously or exogenously inducedparoxysmal ventricular tachycardia (“PVCs”). Still other embodimentsinvolve measuring changes induced by exercise, alteration in heart rateand loading or unloading conditions, and predicting response toelectrophysiological or pharmacological stimuli or interventions.

Optionally, a method may further include measuring the heart cycle usingan electrocardiogram device, with the selected time during the heartcycle being selected using the electrocardiogram measurement. In anotherembodiment, the method may comprise measuring the heart cycle using atleast one sensor on a catheter positioned in the heart chamber, whereinthe selected time during the heart cycle is selected using the sensormeasurement. The timing of various steps may be different in differentembodiments. For example, in one embodiment, the measuring step isperformed immediately after causing a change in at least one of volumeand pressure. In another embodiment, the measuring step is performedduring at least a portion of the heart cycle after the change in atleast one of the volume and pressure. Optionally, the method may furthercomprise causing a change, measuring and calculating steps over a seriesof two or more consecutive heart cycles.

In one embodiment, measuring the change comprises measuring a change inat least one pressure within the heart chamber. For example, measuringthe change in pressure may involve measuring a change in end-diastolicpressure and a change in end-systolic pressure. In such embodiments,calculating the at least one parameter may involve calculating a cardiacpressure reserve, comprising: calculating a first difference between afirst end-systolic pressure and a second end-systolic pressure;calculating a second difference between a first end-diastolic pressureand a second end-diastolic pressure; and dividing the first differenceby the second difference. The method may optionally further includeproviding at least one of the end-diastolic pressures, the end-systolicpressures and the cardiac pressure reserve for display on a displaydevice. For example, the providing step may involve providing data inthe form of a plot, with at least one end-diastolic pressure on one axisof the plot and at least one end-systolic pressure on a perpendicularaxis of the plot. Characteristics and parameters may be measured andcalculated in any heart chamber, but in one embodiment, measuring thechange comprises measuring a change in left ventricular end-diastolicpressure and a change in left ventricular end-systolic pressure.

In another embodiment, measuring the change involves measuring a changein at least one volume within the heart chamber. For example, measuringthe change may include measuring a change in end-diastolic volume and achange in end-systolic volume. In some embodiments, calculating theparameter comprises calculating a volume reserve, which involves:calculating a first difference between a first end-systolic volume and asecond end-systolic volume; calculating a second difference between afirst end-diastolic volume and a second end-diastolic volume; anddividing the first difference by the second difference. The method mayoptionally further include providing at least one of the end-diastolicvolumes, the end-systolic volumes and the volume reserve for display ona display device. For example, the providing step may involve providingdata in the form of a plot, with at least one end-diastblic volume onone axis of the plot and at least one end-systolic volume on aperpendicular axis of the plot. Measuring the change, in someembodiments, involves measuring a change in a left ventricularend-diastolic volume and a change in a left ventricular end-systolicvolume.

In some embodiments, measuring the change comprises measuring a changein at least one pressure and a change in at least one volume within theheart chamber. Measuring the change, for example, may involve measuringa change in end-diastolic volume and a change in end-diastolic pressure.The end-diastolic moment may be determined using the volume sensor, asventricular volume is at a maximum at end-diastole. In this embodiment,the method may further include providing pressure and volume data as aplot, with at least one volume on one axis of the plot and at least onevolume on a perpendicular axis of the plot. Calculating the at least oneparameter may involve calculating a lusitropic stiffness of the heartchamber, which involves: calculating a first difference between a secondend-diastolic pressure and a first end-diastolic pressure; calculating asecond difference between a second end-diastolic volume and a firstend-diastolic volume; and dividing the first difference by the seconddifference. The method may further involve providing at least one of thevolumes, the pressures and the lusitropic stiffness for display on adisplay device. In another embodiment, calculating the at least oneparameter comprises calculating a lusitropic compliance of the heartchamber, which involves: calculating a first difference between a secondend-diastolic volume and a first end-diastolic volume; calculating asecond difference between a second end-diastolic pressure and a firstend-diastolic pressure; and dividing the first difference by the seconddifference. In various embodiments, methods may further includeproviding at least one of the volumes, the pressures and the lusitropiccompliance for display on a display device. In some embodiments,measurements may be taken during isovolumetric relaxation andisovolumetric contraction.

In yet another embodiment, measuring the change comprises measuring achange in end-systolic volume and a change in end-systolic pressure. Theend-systolic moment may be determined using the volume sensor, asventricular volume is at a minimum at end-systole. Some embodiments mayfurther comprise providing volume and pressure data as a plot, with atleast one volume on one axis of the plot and at least one pressure on aperpendicular axis of the plot. Calculating the at least one parameter,in one embodiment, comprises calculating an inotropic stiffness of theheart chamber, which involves: calculating a first difference between asecond end-systolic pressure and a first end-systolic pressure;calculating a second difference between a second end-systolic volume anda first end-systolic volume; and dividing the first difference by thesecond difference. This method may also include providing at least oneof the volumes, the pressures and the inotropic stiffness for display ona display device.

In another embodiment, calculating the at least one parameter comprisescalculating an inotropic compliance of the heart chamber, whichincludes: calculating a first difference between a second end-systolicvolume and a first end-systolic volume; calculating a second differencebetween a second end-systolic pressure and a first end-systolicpressure; and dividing the first difference by the second difference.Again, any of the volumes, the pressures and the inotropic compliancemay be provided for display on a display device.

In another embodiment, the measuring and calculating steps include:continuously measuring a pressure and volume in the heart chamber duringat least two heart cycles, a first of the heart cycles occurring beforethe change-causing step; calculating a first integral of the product ofthe pressure and the volume as the volume increases due to thechange-causing step; calculating a second integral of the product of thepressure and the volume as the volume decreases; and calculating amyocardial work of the heart chamber by subtracting the second integralfrom the first integral. Optionally, this method may further include:calculating a first myocardial work for the first heart cycle;calculating a second myocardial work for a second heart cycle; measuringa first end-diastolic pressure for the first heart cycle and a secondend-diastolic pressure for the second heart cycle; and calculating amyocardial reserve by dividing a difference between the second and firstmyocardial works by a difference between the second and the firstend-diastolic pressures. Such a method may further include: calculatinga body surface area; and calculating a myocardial reserve index bydividing the myocardial reserve by the body surface area. Myocardialwork may be calculated for a left ventricle of a heart, the rightventricle of a heart, or any other chamber.

In yet another embodiment, a method as described above may furtherinclude: measuring a change in at least one flow rate of blood flowingout of the heart chamber which occurs in response to the volume and/orpressure change; and calculating at least one flow-related parameter ofthe heart chamber based on a ratio of the measured change in the flowrate to the volume and/or pressure change. In such embodiments,measuring the change in the flow rate may involve measuring at least oneflow rate in an aorta. Alternatively, measuring the change in the flowrate may involve measuring at least one flow rate in at least onepulmonary artery.

In one embodiment, calculating the flow-related parameter comprisescalculating at least one stroke volume of a heart from which the flowrate is measured, and the method further includes: estimating a firstcardiac output for the heart; measuring a pulse rate of the heart;calculating a first stroke volume by dividing the first cardiac outputby the heart rate; calculating a first integral of the flow rate over anumber of heart cycles; calculating a second stroke volume by dividingthe first integral by the number of heart cycles; calculating a scalingfactor by dividing the first stroke volume by the second stroke volume;calculating a selected integral of the flow rate during a selected heartcycle; and calculating the selected stroke volume by multiplying theselected integral by the scaling factor. In some embodiments, the firstcardiac output is estimated using at least one of Fick's method and adilution method. In some embodiments, the method further includesdetermining a selected cardiac output by dividing the selected strokevolume by a time of duration of the selected heart cycle. The purpose ofthis calibration procedure is to allow the catheter system to measurethe stroke volume and effective cardiac output of each heart cycle.Current methods of Fick or dilution average the cardiac output over manyheart cycles. Such embodiments may additionally involve, for examplemeasuring a body surface area, and calculating a cardiac index bydividing the selected cardiac output by the body surface area.

Some embodiments further include: determining a first selected cardiacoutput and a second selected cardiac output for first and second heartcycles; measuring first end-diastolic pressure and a secondend-diastolic pressure for the first and second heart cycles; andcalculating a cardiac reserve by dividing a difference between thesecond and first selected cardiac outputs by a difference between thesecond and first end-diastolic pressures. For example, the method mayfurther involve: measuring a body surface area, and calculating acardiac reserve index by dividing the calculated cardiac reserve by thebody surface area.

In one embodiment, the method further comprises: calculating a firststroke volume and a second stroke volume for first and second cardiaccycles; measuring first end-diastolic pressure and a secondend-diastolic pressure for the first and second heart cycles; andcalculating a stroke reserve by dividing a difference between the secondand first calculated stroke volumes by a difference between the secondand first end-diastolic pressures. This method may further include:measuring a body surface area; and calculating a stroke volume reserveindex by dividing the calculated stroke volume reserve by the bodysurface area. Optionally, it may further comprise: measuring an averagesystolic pressure in at least one outflow artery adjacent the heart;measuring an average diastolic pressure in the heart chamber;calculating a difference between the average systolic pressure and theaverage diastolic pressure; and calculating a stroke work by multiplyingthe difference by the stroke volume.

In some embodiments, the method further comprises: calculating a firststroke work and a second stroke work for first and second cardiaccycles; measuring first end-diastolic pressure and a secondend-diastolic pressure for the first and second heart cycles; andcalculating a stroke work reserve by dividing a difference between thesecond and first calculated stroke works by a difference between thesecond and first end-diastolic pressures. Optionally, the method mayfurther include: measuring a body surface area; and calculating a strokework reserve index by dividing the calculated stroke work reserve by thebody surface area. The method may also optionally include measuringpost-systolic potentiation and its ability to estimate myocardialreserve.

In the above embodiments, the at least one outflow artery may be anaorta, at least one pulmonary artery, or any other suitable outflowartery. The above embodiments may optionally further involve calculatinga cardiac efficiency by dividing the stroke work by the myocardial work.

In one embodiment, a method includes: calculating a first stroke volumeand a second stroke volume for first and second cardiac cycles;measuring first end-diastolic volume and a second end-diastolic volumefor the first and second heart cycles; and calculating a cardiacamplification by dividing a difference between the second and firstcalculated stroke volumes by a difference between the second and firstend-diastolic volumes.

In another aspect of the invention, a system for measuring one or moreparameters of a heart includes: a catheter comprising at least onesensor and at least one expandable element, usually comprising anactuator for introducing a known volume of constrained or unconstrainedfluid into at least one chamber of the heart at a selected time during aheart cycle to effect a volume change in the heart chamber; a fluidsource coupled with the catheter for providing fluid to the actuator;and a processor coupled with the catheter for processing data sensed bythe at least two sensors. In some embodiments, the sensor may include atleast one of a pressure sensor and a volume sensor. Optionally, thesensor may further comprises at least one of a flow sensor for measuringblood flowing from the heart and a vascular pressure sensor formeasuring pressure in a vessel extending from the heart. Alternatively,the catheter could comprise a means for deforming a heart chamber, suchas a pusher for outwardly deflecting or otherwise mechanically reshapingthe heart chamber to induce a change in pressure or change in volume. Inone embodiment, a flow meter may be included to measure distensibiltycharacteristics of a heart chamber.

In some embodiments, the flow sensor or pressure sensor is disposed in alocation to measure flow or pressure in at least one of an aorta and apulmonary artery. In some embodiments, at least one sensor comprises ahydrophone. In some embodiments, the sensor comprises at least oneultrasound transducer for measuring a distance within a chamber of theheart. In some embodiments, for example, the ultrasound transducercomprises: a first pair of ultrasound transducers coupled with thecatheter in parallel with a longitudinal axis of the catheter formeasuring a first distance between the transducers and the wall of theheart chamber; a second pair of ultrasound transducers coupled with thecatheter in an orientation 90-degrees rotated from the first pair oftransducers for measuring second and third distances to a wall of theheart chamber; and a third pair of ultrasound transducers coupled withthe catheter in an orientation 90-degrees rotated from the first andsecond pairs of transducers for measuring fourth and fifth distances toa wall of the heart chamber.

Any actuator may be suitable for use in the system. For example, anactuator may comprise at least one of a fluid outlet port and anexpandable balloon, the expandable balloon being expandable byintroducing the fluid into the balloon. In some embodiments, the systemfurther includes an electrocardiogram device coupled with the processorfor measuring the heart cycle

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a catheter-based cardiac performance monitoringsystem in accordance with the principles of the present invention.

FIG. 2 is a schematic illustration of the system according to FIG. 1,including interfaces between various components of the system.

FIG. 3 illustrates a patient's heart with a catheter in place, havingmultiple sensors and an actuator, according to one embodiment of thepresent invention.

FIG. 4A illustrates a pressure/volume curve which may be derivedaccording to principles of the present invention in some embodiments.

FIG. 4B illustrates a stroke work/pressure curve which may be derivedaccording to principles of the present invention in some embodiments.

FIG. 5A illustrates an induced change in pressure/volume curves whichmay be derived in some embodiments, according to principles of thepresent invention.

FIG. 5B illustrates the induced change according to FIG. 5A in a strokework/pressure curve.

FIG. 6 illustrates a change in pressure in a heart chamber over time,the change induced by an actuator according to principles of the presentinvention.

FIG. 7. illustrates data such as shown in FIG. 7 after passing through alow-pass filter according to principles of the present invention.

FIG. 8 illustrates data such as shown in FIGS. 6 and 7 after passingthrough a high-pass filter according to principles of the presentinvention.

FIG. 9 illustrates stiffness of a heart chamber over time, as derivedfrom data such as that illustrated in FIGS. 6-8 according to principlesof the present invention.

FIG. 10 illustrates a sensor having multiple ultrasound transducers, asmay be used in an embodiment of the present invention.

FIG. 11 illustrates a catheter in place in a patient's heart, having anultrasound sensor such as the one illustrated in FIG. 10.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed at methods, systems, and apparatus formonitoring one or more patient parameters, particularly cardiacperformance parameters. The apparatus of the present invention typicallyincludes a catheter having one or more sensors and one or moreactuators. One such catheter, for example, is described in U.S. patentapplication Ser. No. 10/734,490, entitled “Method and System forMonitoring and Treating Hemodynamic Parameters,” previously incorporatedby reference. Systems of the present invention typically include acatheter, an external actuation device, and a controller. In someembodiments, systems may also include an electrocardiogram (ECG) device,other similar heart monitoring device(s), thermistors, cardiac outputmeasuring consoles, injector devices, phonocardiography devices or thelike for use in conjunction with the catheter. Additionally, someembodiments may employ one or more implantable devices, such as thosedescribed in A monitoring device such as those described in U.S. patentapplication Ser. No. 10/734,490, entitled “Method and System for RemoteHemodynamic Monitoring,” which was previously incorporated by reference.Methods of the present invention generally involved causing a change ina characteristic of a heart, measuring the change, and calculating acardiac parameter based on the change.

Referring now to FIG. 1, an exemplary system 100 constructed inaccordance with the principles of the present invention comprises acatheter device 102 placed in a heart H of a patient P, a controller 108coupled with catheter device 102, and an external actuator 110 coupledwith controller 108 and catheter device 102. As will be describedfurther below, catheter device 102 typically includes one or moresensors 104 and one or more actuators 106 and can be placed in anysuitable location in the heart H or vasculature. Sensors 104 may beadapted to measure a variety of physiological parameters characteristicof heart function, while actuators 106 may be adapted to effect a changewithin a chamber, multiple chambers, or other areas in or around theheart H. Controller 108 typically receives data from sensors 104 andalso activates various components of catheter 102, as well as externalactuator 110. Controller 108 may also receive data from other variouscomponents, such as an ECG device. External actuator 110 generallyactivates one or more actuators 106 on catheter 102, via instructionsfrom controller 108.

Systems according to the present invention may take a variety ofspecific forms, including both specialized and off-the-shelf equipment.Components shown in FIG. 1 may be combined and/or additional componentsmay be added to system 100. Usually, the catheter device 102 will bespecially fabricated in accordance with the principles of the presentinvention, although it may be possible, in some instances, to employmore conventional sensor devices which may be commercially acquired nowor in the future. Furthermore, the external controller 108 or externalactuator 110 may at least partly comprise commercially availableequipment. Often, general purpose computers and workstations may beprogrammed to perform many of the functions and calculations of thesystems and methods of the present inventions.

Referring now to FIG. 2, the various components of system 100illustrated in FIG. 1, as well as an ECG device 210, are shown witharrows designating directions in which data may flow between componentsof system 100 in some embodiments. For example, data may flow fromcontroller 108 to catheter 102, such as data activating one or moresensors, energy may be transmitted from controller 108 to catheter 102and the like. Catheter 102 may, in turn, transmit sensed data tocontroller 108. External actuator 110 may receive data from controller108, telling it when to activate one or more actuators on catheter 102.An ECG device 112 may be activated by controller 108 and may providecardiac data to controller 108 which may be used by controller 108 tooperate other components of system 100. Generally, any suitableconnectivity and transmission of data, energy, and the like between anysuitable components of system 100 is contemplated within the scope ofthe present invention.

The external controller 108 may provide direct user input/outputcapabilities, i.e., including screens, printer interfaces, read/writedata storage capabilities, etc. Optionally, the external controller 108may require interface with a further computer, workstation, or otherdevice which interfaces directly with the user and provides theinput/output capabilities. In all cases, the external controller 108 mayprovide data input/output connections shown schematically as line 120.

Referring now to FIG. 3, catheter 102 for placement in a heart H maytake a variety of forms. Again, for further description of an exemplarycatheter which may be used in the methods of the present invention,reference may be made to U.S. patent application Ser. No. 10/734,490,entitled “Method and System for Monitoring and Treating HemodynamicParameters,” previously incorporated by reference. In other embodiments,other catheters may be used and/or multiple catheters may be usedsimultaneously or in conjunction. Catheter 102 may be placed in anysuitable location. In FIG. 3, catheter 102 is shown descending throughthe aorta into the left ventricle of the heart H, with sensors both inthe aorta and in the left ventricle. Alternatively, catheter could beplaced in the right side of the heart, sensors could be positioned inmultiple heart chambers, actuators could be placed in the aorta,pulmonary artery, or inferior vena cava, and/or the like. Thus, althoughcatheter 102 is shown in the left ventricle and is often described belowin terms of measuring left ventricular function, catheter 102 and system100 of the present invention may be placed in any suitable portion ofthe heart and/or structures surrounding the heart.

Catheter 102 may generally include any suitable combination of sensorsand actuators, and the sensors and actuators may be disposed alongcatheter 102 at any desired locations. In FIG. 3, for example, sensorsinclude a flow sensor 130, an electrical conductivity sensor 131,multiple pressure sensors 132 aligned in a linear array, an ultrasoundsensor 134 comprising a rotated cube having multiple ultrasoundtransducers, and a hydrophone 138. Also included on catheter is anactuator, which may comprise a volume actuator, pressure actuator or thelike. Volume actuators may include one or more fluid injection ports,one or more fluid aspiration ports, an inflatable balloon, a combinationthereof, and/or the like. Some embodiments may also include one or morethermistors.

Methods of the present invention generally involve inducing a change ina characteristic of a heart or heart chamber, measuring the change, andcalculating a parameter that changes due to the measured change.Oftentimes, the changed characteristic will be either pressure, volume,or both, and the change will typically be induced by one or moreactuators on the catheter. Of course, multiple changes and/or othertypes of changes may be induced and measured, and multiple parametersmay be calculated in any given procedure or method. Such other types ofchanged characteristics may include but are not limited to changes inflow, oxygen content, content of any other suitable gas such as carbondioxide, dimensions of a chamber or wall thickness or the like,temperature, and the like. The calculated parameter (or parameters) willoften provide valuable diagnostic information regarding a patient'sheart function and performance, to allow a physician to make accuratediagnoses and patient specific treatment decisions, such as whether totreat a patient pharmaceutically, with device intervention, withsurgery, or with none or some combination thereof.

In some embodiments, the catheter system is used to measure variousproperties of the heart throughout a cardiac cycle, changing the volumeand pressure of a cardiac chamber using actuation means, and measuringthe immediate and cyclical responses to this change. Some myocardialproperties are described by the response at a single point in time tothe actuation means: the ratio of the change of one parameter over thechange of some other parameter induced by the actuation means.Ventricular compliance, for example, is the immediate change inventricular pressure induced by a change in ventricular volume. Aorticvalvular gradient reserve, a further example, is the change in themaximum aortic trans-valvular pressure gradient measured at the point ofmaximum aortic flow, the change of which results from a modified LVEDP.Other cardiac properties are described by the cyclical output of theheart following two different “initial” conditions. In this context,“initial conditions” is defined as those conditions that exist in theventricle (or other heart chamber) at End Diastole, the point in timewhen the ventricle begins to contract. Cardiac Reserve, for example, isthe increase in cardiac output induced by an increase in LVEDP.Similarly, methods of the present invention may be used to derive the“reserve” of a number of cardiac properties. In this context, “reserve”describes the change in a property due to a change in the inducingconditions.

For example, in one embodiment a catheter may be used to measure inreal-time the pressure and volume of the left ventricle. The cathetermay also be capable of measuring in real-time the blood flow ratethrough the aorta. From these measurements the catheter system cancalculate the left ventricular end-diastolic pressure (LVEDP), leftventricular end-diastolic volume LVEDV, left ventricular end-systolicpressure LVESP, left ventricular end-diastolic volume LVESV, cycle time(heart rate), change in pressure divided by change in time (dP/dt),regurgitation in the aortic and mitral valves, and/or the ejectionfraction of the heart for each cycle. Based on the data sensed by thecatheter, the system may also calculate, display and record thePressure-Volume loop of the left ventricle. An optional right catheter,when used, allows simultaneous measurements of the right atrial and/orright-sided ventricular pressure. With these measurements, the systemmay be used to determine the pulmonary vascular resistance (PVR) and thesystemic vascular resistance (SVR) for each cycle.

Methods of the present invention also typically involve effecting achange in the volume or pressure in a heart chamber. By effecting such achange and measuring the change, various cardiac parameters may bemeasured in furtherance of accurate cardiac diagnosis andcharacterization. In one embodiment, the catheter is used to add fluidto the ventricle during diastole to increase end diastolic pressure andvolume. Alternatively or additionally, a balloon placed in the ventriclemay be inflated or deflated during diastole to adjust the end-diastolicpressure and volume. In another embodiment, a hydrophone transmitter maybe used to alter volume in a heart chamber. An actuator such as ahydrophone may be used to effect volume changes at a rapid rate, such as100 or more times per second. In still other embodiments, the afterloadof a heart may be modified, either in addition to one of the methodsdescribed above or alone. For example, an inflatable balloon positionedin the aorta may be inflated to increase afterload. Similarly, preloadmay be modified, using apparatus such as an inflatable balloonpositioned in the inferior vena cava or right atrium. Finally, theinitial conditions of the heart may be modified pharmaceutically byinjecting various agents into the blood stream or by exercising thepatient through, for example, lifting saline bags or by generatingPreventricular Contractions, (PVC's) which in general have a lower thanusual end diastolic volume and the cycle immediately following PVC's,which in general have a higher than usual end-diastolic volume and morevigorous contraction. This latter method, cardiac response to a PVC,illustrates the value of the ability to measure stroke volume on aper-cycle basis. The many suitable methods may be used to effect avolume and/or pressure change in one or more chambers of a heart, inorder to arrive at useful cardiac parameter data.

By effecting a change in volume or pressure in a heart chamber,measuring the change in a parameter that is effected by the change, andcalculating a parameter based on the change, methods of the presentinvention may be used to derive novel parameters that may be used tohelp characterize a patient's heart in quantitative terms. Bycalculating a ratio of the increase in stroke volume over the increasein end-diastolic pressure, for example, the system calculates a measureof cardiac reserve. In another example, a parameter called cardiacamplification may be measured as the ratio of the increase in strokevolume to the increase in end-diastolic volume. In yet another example,continuous measurement of compliance may be obtained by calculating theratio of change in pressure caused by a change in volume.

As discussed above, any suitable combination of sensors may be disposedalong a catheter of the present invention to measure any of a number ofsuitable cardiac parameters. For example, absolute pressure may bemeasured by one or more sensors. Such pressure sensors, for example, mayhave a frequency response of at least 100 Hz in some embodiments. In oneembodiment, at least one pressure sensor is located near the distal endof the catheter, a second pressure sensor is located on the catheter toallow the sensor to be positioned just proximal to the aortic valve(when the catheter is positioned in the left ventricle), and a thirdpressure sensor is located outside the body of the patient to detectatmospheric pressure. In other embodiments, the third, atmosphericsensor may be eliminated, atmospheric pressure may be alternativelymeasured on the external computation device (the interface “box”),additional sensors may be added, positions of sensors may be changed,and/or the like. In some embodiments, for example, one or more sensorsmay be used to measure transthoracic pressure, which changes whenbreathing, which is particularly important when diagnosing tamponade, orto measure a finer spatial pressure gradient across the aortic valve andinto the left ventricle, which is particularly important whendifferentially diagnosing aortic stenosis (AS) and hypertrophicobstructive cardiomyopathy (HOCM) as well as hypertrophicnon-obstructive cardiomyopathy (HNOCM).

Volume measurement in a heart chamber such as the left ventricle may beaccomplished by any of a variety of sensors and methods. In oneembodiment, a sensor comprising six ultrasound transducers mountedorthogonal to each other is used to measure six orthogonal radii ofcurvature of an assumed ovoid shape of the heart. These measurements maybe used to determine multiple estimates of the ventricular volume at anysuitable interval, such as once every heart cycle or even multiple timesper second. An alternative embodiment uses a phased array ultrasonicsystem to measure the cross-sectional area of a heart chamber atmultiple points along it's axis throughout a heart cycle to compute ameasurement of volume using Taylor's theorem. Yet another embodimentemploys the release of a known amount of dye or electrically conductiveliquid, whose concentration is then measured to estimate the volume ofblood into which it was diluted. A further method involves themeasurement of the conductivity of the blood in the ventricle, commonlyreferred to as conductance plethysmography.

Catheters and systems of the invention can be used to calculate cardiacoutput, which may be averaged over a number of cycles. Such calculationsmay be made using any suitable method, such as thermal dilution, dyedilution, conduction dilution, or Fick's method using oxygenconsumption.

Another parameter which may be measured is blood velocity, such as bloodvelocity in the aorta or in one or more pulmonary arteries. Any suitablemeasurement method may be used, including thermal dilution, shear forcemeasurement, a pitot-tube method (stagnant v. dynamic flow), Dopplerultrasound, or any other suitable methods, including methods not yetdiscovered. By integrating blood velocity throughout a cardiac cycle,the system may be used to derive a stroke volume for each cycle. Strokevolume per cycle may then be used, with measured heart rate, tocalculate per-cycle cardiac output. This per-cycle value of cardiacoutput may be calibrated using the cardiac output measuring system.

In many embodiments, a catheter has the ability to modify the volumeand/or pressure in a heart chamber by introducing and/or removing fluidvia actuator 106. In some embodiments, fluid may be introduced and/orremoved during diastole to change the end diastolic pressure and/orvolume. In other embodiments, actuator 106 may rapidly expand orcontract or introduce and remove the same amount repeatedly during anentire cycle of the heart. In some embodiments, such rapidintroductions/removals may occur at a rate of greater than 100 Hz butless than 1000 Hz, although other rates are contemplated within thescope of the invention. In one embodiment, external volume actuator 110,such as a pump, is coupled with catheter 102 to perform the introductionand/or removal functions. Altematively, external actuator 110 mayperform introduction or withdrawal of large quantities of fluid to altercardiac output, while actuator 106 on the catheter performs a higherfrequency modulation.

As is discussed above, various embodiments of devices and methods of thepresent invention may include any suitable combination of one or moreactuator and one or more sensor. For example, a catheter that includesone pressure sensor 104 and one actuator 106, the latter coupled to anexternal actuator 110, may be used to measure at least an increase inleft ventricular end-systolic pressure with increasing left ventricularend-diastolic pressure. This measurement provides one means forcharacterizing cardiac reserve, referred to above as pressure reserve.Thus, the preceding and following descriptions of specific systems,devices, and/or methods for measuring and calculating cardiac parametersshould not be interpreted to limit the scope of the invention in anyway, but are provided for exemplary purposes only.

Actuator 106 may be used to modify the pressure and/or volume in a heartchamber at one or more precise times during a cardiac cycle. In oneembodiment, actuator 106 provides such modifications by delivering afluid (gas or liquid) into or out of the chamber. Delivery may comprisedirect delivery of fluid into the chamber, such as through one or moreapertures in actuator 106. Alternatively, fluid may be introduced via aninflatable balloon or similar structure. The timing of fluid deliveriesand/or withdrawals may be coordinated by controller 108, which may usedata from one or more sensors 104, an optional ECG system 112, and/orthe like. The controller 108 may also perform other digital signalprocessing, memory, and display functions. A display may be used topresent one or more novel parameters to a doctor or other user,including but not limited to the various property and reserve parametersdescribed below.

In addition to many known cardiac parameters, such as cardiac output andventricular pressure, catheter devices and methods of the presentinvention provide for measurement of additional parameters that have notbeen previously measured. A table (Table 1) summarizing some of these ispresented below. Others parameters may also be measured or calculated,such as the inverse of a parameter or the use of the parameter for aspecific chamber or valve. Thus, the following table is not exhaustive.TABLE 1 Name Variable Equation Description Left Ventricle Pressure LVPMeasured directly Gauge pressure in Left Ventricle Left VentricularVolume LVV Measured directly Volume of left ventricle End diastolicvolume EDV Measured directly Volume of chamber when

volume is maximum End systolic volume ESV Measured directly Volume ofchamber when

volume is minimum End diastolic pressure EDP Direct measurement GaugePressure in

chamber when volume is

maximum End systolic pressure ESP Direct measurement Gauge Pressure in

chamber when volume is

minimum Aortic Pressure AOP Direct measurement Gauge Pressure in aorta

just distal to Aortic Valve Ejection Fraction EF (EDV-ESV)/EDV Describesthe percentage

of blood ejected from a

chamber (usually LV)

during a cycle Cardiac Output CO Fick or dilution Total amount of blood

or k * ∫Velocity * HR pumped by the heart per

minute Cardiac Index CI CO/BSA Cardiac output normalized

by Body Surface Area Stroke Volume SV CO/HR Net amount of blood

or ejected into aorta in one

k * ∫Velocity cycle. Measured either

from cardiac output or

from the integral of

calibrated blood velocity

during a cycle. Stroke Volume Index SVI SV/BSA Stroke volume normalized

by Body Surface Area Pressure Reserve PR d(LVESP)/d(LVEDP) Marginalchange in end

systolic pressure due to a

marginal change in end-

diastolic pressure Volume Reserve VR d(LVESV)/d(LVEDV) Marginal changein end

systolic volume due to a

marginal change in end-

diastolic volume Cardiac Reserve CR d(CO)/d(LVEDP) Marginal increase in

cardiac output due to a

marginal increase in

LVEDP Cardiac Reserve Index CRI d(CI)/d(LVEDP) Cardiac Reserve

normalized by Body

Surface Area Stroke Reserve SR d(SV)/d(LVEDP) Marginal increase in

stroke volume due to a

marginal increase in

LVEDP Stroke Reserve Index SRI d(SVI)/d(LVEDP) Stroke Reserve normalized

by Body Surface Area Myocardial Work MyW∫_(dV/dt < 0)P  𝕕v − ∫_(dV/dt > 0)P  𝕕v Work performed by

myocardial tissue during a

single cycle Myocardial Work Moment MyWM∫_(dV/dt < 0)PV  𝕕v − ∫_(dV/dt > 0)PV  𝕕v Work moment performed

by myocardial tissue

during a single cycle Myocardial Work Index MyWI MW/BSA Myocardial work

normalized by Body

Surface Area Myocardial Reserve MyR d(MW)/d(LVEDP) Marginal increase in

myocardial reserve due to

a marginal increase in

LVEDP Myocardial Reserve Index MyRI d(MWI)/d(LVEDP) Myocardial Reserve

normalized by Body

Surface Area Stroke Work SW${SV}*( {\overset{\_}{{AOP}_{Systole}} - \overset{\_}{{LVP}_{Diastole}}} )$Hemodynamic work

performed by the left

ventricle during a single

cycle Stroke Work Index SWI SW/BSA Stroke Work normalized

by Body Surface Area Stroke Work Reserve SWR d(SW)/d(LVEDP) Marginalincrease in

Stroke Work due to a

marginal increase in

LVEDP Stroke Work Reserve SWRI SWR/BSA Stroke Work Reserve

Index normalized by Body

Surface Area Systolic Ejection Period SEP Direct measurement Time duringwhich blood

is ejected from LV into

Aorta Stroke Power SP SW/SEP Power performed by heart

against circulatory system Stroke Power Index SPI SP/BSA Stroke Powernormalized

by Body Surface Area Stroke Power Reserve SPR d(SP)/d(LVEDP) Marginalincrease Stroke

Power due to a marginal

increase in LVEDP Stroke Power Reserve SPRI SPR/BSA Stroke Power Reserve

normalized by body

surface areas Myocardial Power MyP MyW/SEP Power performed by the

myocardia during systole Myocardial Power Index MyPI MyP/BSA MyocardialPower

normalized by body

surface area Myocardial Power Reserve MyPR d(MyP)/d(LVEDP) Marginalincrease in

myocardial power due to a

marginal increase in end

diastolic pressure Myocardial Power Reserve MyPRI MyPR/BSA MyocardialPower reserve

Index normalized by body

surface area Myocardial Power MyPSV MyP/SV Power required to deliver

Requirement unit stroke volume Ejection contractility EC$\frac{{P_{2}V_{2}} - {P_{1}V_{1}}}{( {t_{2} - t_{1}} ){\int_{t_{1}}^{t_{2}}{Q\quad{\mathbb{d}t}}}}$Instantaneous power over

instantaneous stroke

volume (units: dP/dt) Cardiac Efficiency CE SW/M_(Y)W Efficiency of theheart in

converting myocardial

work into circulatory work Cardiac Amplification CA d(SV)/d(LVEDV)Marginal increase in

stroke volume due to a

marginal increase in

LVEDV Valvular Gradient VG ΔPmax Maximum (during a cycle)

pressure gradient across a

valve Valvular Gradient Reserve VGR d(VG)/d(LVEDP) Increase in VG as a

function of increase in

LVEDP. Valvular Area VA 0.11 * SV√ΔP Standard calculation of

valvular area using mean

pressure gradient and

mean flow rate Valvular Area Reserve VAR d(VA)/d(LVEDP) Increase invalvular area

as a function of increase

in LVEDP Valvular Regurgitation VR ∫Q_(REGURGITATION) CumulativeregurgitanT

flow during a cycle Valvular Regurgitation VRR d(VR)/d(LVEDP) Increasein regurgitanT

Reserve flow as a function of

increase in LVEDP

Some of the methods for measuring and calculating cardiac parametersaccording to principles of the present invention are described below.These methods are not an exhaustive list of the methods which may beemployed according to the present invention as described in the appendedclaims.

Exemplary Methods for Determining Left Ventricular End-DiastolicPressure (LVEDP), Left Ventricular End-Systolic Pressure (LVESP), andAortic Pressure (AOP)

In one embodiment, catheter 102 maybe used in a left heartcatheterization procedure, and thus measure cardiac parameters relatingto the left ventricle. Other embodiments, however, may be optimized forother chambers of the heart and, thus, may measure parameters in one ormore of the other three chambers of the heart. Thus, LVEDP and EDP (EndDiastolic Pressure) may be occasionally used interchangeably in thisapplication, as LVEDP is merely one example of EDP.

In one embodiment, LVP (Left Ventricular Pressure) may be measured usinga microfabricated pressure sensor attached to the catheter andintroduced into the left ventricle. In alternate embodiments, anexternal pressure sensor is hydraulically linked by a lumen in thecatheter to the body fluids of the left ventricle. Similarly, AOP ismeasured in some embodiments using a second microfabricated pressuresensor attached to the catheter. In alternate embodiments, AOP may bemeasured with the first microfabricated sensor or an external pressuresensor hydraulically linked to the aorta.

One method of determining LVEDP is to record left ventricular pressure(LVP) at point in time when left ventricular volume (LVV) is at amaximum, that is, just as the ventricle is about to contract. Analternate method comprises recording LVP at the “R” wave of the Q-R-Scomplex of an electrocardiogram (ECG). Another alternative comprisesmonitoring the left ventricular pressure continuously and using apattern recognition algorithm to find the pressure when change inpressure divided by change in time equals zero (dP/dt=0) and d²P/dt₂is >0 just before dP/dt becomes maximum. Still another alternativemethod for determining LVEDP is to measure the pressure when the “first”heart sound “S1” stops, which occurs when the mitral valve is closed. Toobtain the heart sounds, a pressure sensor may be used to sample thepressure signal at about 2000 times per second (or any other suitablefrequency) and filter out the lower frequency components associated withincrease in blood pressure. Alternatively, the catheter may employ adedicated hydrophone for monitoring acoustic signals emanating fromvalves, intracaridac defects which produce shunts, regurgitant lesionsor the like.

One method of determining LVESP is to record LVP when LVV is at aminimum, which is the point of minimum left ventricular volume. Anothermethod of determining LVESP is to record LVP when the blood velocity inthe aorta first becomes zero after reaching a maximum positive number,which is the point at which blood first stops flowing into the aorta. Asignificant difference between these two values might indicate and allowquantification of mitral regurgitant flow (or flow through shunts to theright side) after the aortic valve closes. An alternative method wouldbe to record LVP when the “T” wave on the ECG has just ended. Thepressures measured these three ways should give nearly identicalresults; therefore a comparison of any differences might help indicate aphysiological abnormality. Another alternative method involvescalculating a regurgitant fraction.

Method for Determining Left Ventricular End-Diastolic Volume

One currently used method for determining LVEDV employs one or morex-ray images of the heart and a manual drawing of the ventricularperimeter using an electronic cursor. These outlines are then used inconjunction with an empirical estimating formula to calculate anestimate of the heart's volume at end diastole. This technique iscumbersome and time consuming, making it impractical for estimatingnumerous end-diastolic volumes. In addition, since only one or twoprojections of the heart are used, a significant error is implied in themeasurement. Furthermore, the formulae used in such techniques forcalculating volume do not accurately reflect true volume.

Another currently available technique uses an external ultrasoundtransducer to image the whole heart and also measure volume. This is afairly accurate technique, but since the ultrasound transducer isoutside the body, it is incapable of simultaneously measuring pressureor changing end diastolic pressure. In addition, not all patients haveanatomy which is amenable to an ultrasonic imaging systemtransthoracically. Nevertheless, this approach could be used inconjunction (simultaneously) with a catheter that doesn't feature thevolume-measuring capability.

In one embodiment of the present invention, a method of measuringvolumes in body cavities such as a heart chamber, involves using sixultrasound transducers mounted orthogonally to each other, as shown inFIG. 10. Two of the transducers are mounted parallel to the catheter andthus measure a distance perpendicular to the axis of the catheter. Theother four transducers are mounted in pairs on surfaces that are axially90 degrees rotated from the first pair of sensors but also tilted 45degrees up or down. Thus, the latter four transducers measure thedistance between them and the wall of a heart chamber in four directionswhich are all orthogonal to each other. Another way of describing thearrangement is that of six transducers each mounted on a face of a cube.The cube is then rotated 45 degrees about one of the faces and mountedover a catheter body. To facilitate manufacturing of the catheter whilekeeping a slim profile, the cube may be “disassembled,” i.e., thetransducer pairs are not necessarily contiguous. The transducer assemblymight also be part of an inflatable or expandable assembly to projectinto the ventricle somewhat during measurement.

An alternative method for measuring ventricular volumes is to use aphased array ultrasonic imaging system with circular electrodes, i.e.rings about the catheter. These rings may be excited slightly out ofphase with each other to send the wave up or down relative to theperpendicular of the catheter. The signals returning to the rings wouldbe distributed over time, depending upon the distance from the catheterto the ventricular wall in the various segments of the ring. Thus, theamplitude over time of the reflected signal would correspond to thevarious radial distances between the catheter and the wall of the heartchamber. Making numerous measurements at various angles from normal in avery short period, the system makes multiple cross-sectional areameasurements of the ventricle that are then added using Taylor's methodfor estimating volumes (similar to what is done using externalultrasonic arrays). Yet a third method of measuring ventricular volumeswould be to use two pairs of planar phased array sensors, each parallelpair perpendicular to the other, so that four sides of a catheter aremounted with a phased array transducer. Each of the sensors may, asabove, measure a distance to the wall in order to measure, at any givenangle from the transducers, four radii to the ventricular wall. Taylor'smethod is then used as before to estimate true ventricular volume.

One method of estimating LVEDV is to record LVV, measured using one ofthe above methods, at the point of time when it is at a maximum. In analternative method, an array of electrical conductance sensors on thecatheter is used to determine the average conductance of the ventricularblood. A volume of liquid with a known and different electricalconductivity is dispersed into the left ventricle during diastole. Atend diastole and during systole, the conductivity in the ventricle ismonitored. These measurements produce an estimate of the dilutedelectrical conductance of the ventricular blood. Then, knowing thevolume of injected blood (V_(I)), the electrical conductance of theinjected blood (k_(I)), the conductance of the undiluted blood (k_(B)),and the conductance of the diluted blood (k_(D)), one may compute theend diastolic volume using the following equation:$V_{D} = {V_{I}\frac{k_{I} - k_{B}}{k_{D} - k_{B}}}$

Another method of estimating end diastolic volume uses an array oftemperature sensors on the catheter to determine the temperature of theblood. A quantity of blood at a lower temperature is injected into theventricle during diastole. The temperature of the diluent may bemeasured just before it leaves the catheter, to improve accuracy. Then,knowing the volume of injected blood (V_(I)), the specific heat of theblood (C_(B)), the specific heat of the diluent (C_(I)), the undilutedtemperature of blood (T_(B)), the temperature of the diluent (T_(I)),and the average temperature of the diluted blood at end diastole(T_(D)), the end diastolic volume (V_(D)) is given by the followingequation:$V_{D} = {V_{I}( {1 + \frac{C_{I}( {T_{D} - T_{I}} )}{C_{B}( {T_{B} - T_{D}} )}} )}$

In another embodiment, a method of estimating end diastolic volume usesan array of light sources and optical sensors, perhaps incorporatingoptical fibers. A volume of a solution containing a dye of a knownconcentration is injected and dispersed into the ventricle duringdiastole. The concentration of dye in the blood may be measured usingeither absorption or fluorescent techniques. A dye may be any marker,such as a liquid, gas, other fluid or the like. A fluorescent technique,for example, would entail shining light of one wavelength into the bloodand detecting the intensity of light at a different (fluorescent)wavelength. The concentration of dye in the blood would be a linearfunction of the ratio of the intensity of the fluorescent light over theintensity of the exciting light. Then, knowing the volume of injectedblood (V_(I)), the concentration of dye in the undiluted blood (D_(B)),the concentration of dye in the diluent (D_(I)), and the averageconcentration of dye in the diluted blood at end diastole (D_(D)), theend diastolic volume (V_(D)) is given by the following equation:$V_{D} = {V_{I}\frac{D_{B} - D_{I}}{D_{B} - D_{D}}}$

In other embodiments, it may be useful to determine an end-diastolicvolume without introducing fluid to the ventricle. In some embodiments,it may even be useful to reduce the end-diastolic volume orend-diastolic pressure from the resting value. To accomplish this, acatheter may include a balloon that can hold at least as much volume asthe diluent (either thermal, conductive, or dye diluent or none ifultrasound is used to measure volume, as in the preferred method). Theballoon is first inflated in the ventricle during the systolic phase ofthe previous cycle, helping to eject a corresponding amount of bloodfrom the ventricle. To determine the end-diastolic volume withoutinfluencing it, the balloon is simultaneously and completely deflatedduring diastole by a volume equal to the volume of diluent injected intothe ventricle at the same time. Thus, as the balloon shrinks, thediluent is added to the ventricle without increasing or decreasing thepressure in the ventricle. It may be useful to decrease theend-diastolic volume and/or end-diastolic pressure from an at-rest statewhile determining the end-diastolic volume. This may be accomplished byfirst inflating the balloon during the systolic phase or, in the case ofrepeated cycles, just after the aortic valve has closed. Then, duringdiastolic filling of the ventricle, an amount of diluent is dispersedinto the ventricle. The balloon is simultaneously and completelydeflated by a volume greater than the volume of diluent added, reducingthe end diastolic pressure and volume. The end-diastolic volume isdetermined using one of the dilution methods described above. In oneembodiment, one or more ultrasound transducers are used to measure theventricular volume continuously while the balloon is inflated duringsystole and deflated in diastole to reduce the end-diastolic pressuresand/or volumes.

Methods for Determining End-Systolic Volume

One method for measuring LVESV is to record LVV when it is at a minimum,using one of the continuous volume measuring systems. An alternativemethod for measuring for LVESV is that LVV when aortic flow rate isfirst zero following its maximum. The difference in volumes of these tworecordings is equal to the combination of mitral regurgitant flow andleft-to-right shunt flow after the aortic valve is closed.

Methods for Determining Ejection Fraction

Ejection Fraction is typically defined as the ratio of the differencebetween end-diastolic volume and end-systolic volume over end-diastolicvolume. This calculation may be made, using any of the above-describedmethods of measuring EDV and ESV.

Methods for Determining Cardiac Output Cardiac Index, Stroke Volume, andStroke Volume Index on a Per-Stroke Basis

In one embodiment, a blood velocity or flow rate sensor is coupled withthe catheter and inserted into the aorta. This sensor samples thevelocity of blood at regular intervals, such as approximately once everymillisecond, and transmits that information to a controller or otherprocessor. The controller then determines the average blood velocity byaveraging the readings taken over a second (or some other similar periodof time that is representative of the next step). During that samplingtime, the cardiac output is independently measured using one of theaccepted methods, such as Fick's Law using oxygen consumption or adilution method (thermal dilution, conductance dilution or dilution witha marker, such as a gas, other fluid, liquid, dye or the like).(Grossman's Cardiac Catheterization and Angiography, pp. 101-117describes these methods in detail). The cardiac output thus measured isdivided by the average velocity or flow rate to determine a scalingcoefficient. This coefficient assumes that the aortic cross section nearthe velocity or flow rate sensor is reasonably constant during thesampled cycle and successive cycles. A number of different methods ofmeasuring blood velocity or flow rate are possible, including thermaldilution, shear force measurement, a pitot-tube method (stagnant versusdynamic flow), Ultrasound Doppler, and/or any other suitable method.Once the scaling factor has been determined, the stroke volume may bedetermined for any given cycle and is equal to the product of thescaling factor and the integral of velocity through that cycle. Thestroke time is also calculated as that period between successiveend-diastolic events. Cardiac output is then calculated as the ratiobetween stroke volume over stroke time, adjusted to correct units.Cardiac index is cardiac output divided by body surface area (BSA),which is a known value based on a patient's height and weight. Strokevolume index is stroke volume divided by BSA.

Methods for Determining Cardiac Reserve and Cardiac Reserve Index

In one embodiment, a method for measuring cardiac reserve involves firstmeasuring LVEDP and/or LVEDV at the beginning of one cardiac cycle andthen measuring the cardiac output during that cycle using the methodsdescribed above. This measurement may be repeated any number of timesand multiple data pairs (LVEDP, CO) may be taken. Then, an amount offluid is injected into the left ventricle during a diastole period andthe resulting end-diastolic pressure recorded. The cardiac output forthat cycle is recorded using the methods described above and a new datapoint (LVEDP, CO) is recorded. This process is repeated as desired tocreate a set (n>=2) of data pairs. A line of regression is then fitthrough the data points using a least-squares technique. The slope ofthat line is equal to cardiac reserve. Cardiac reserve index is equal tocardiac reserve divided by BSA.

Methods for Determining Stroke Reserve and Stroke Reserve Index

One method of measuring cardiac reserve is to first measure the LVEDPand the beginning of one cardiac cycle and then measuring stroke volumeduring that cycle using the methods described above. This measurementmay be repeated any number of times and multiple data pairs (LVEDP, SV)taken. Then, an amount of fluid is injected into the left ventricleduring a diastole period and the resulting end-diastolic pressurerecorded. The stroke volume for that cycle is recorded using the methodsdescribed above and a new data point (LVEDP, SV) is recorded. Thisprocess is repeated as desired to create a set (n>=2) of data pairs. Aline of regression is then fit through the data points using aleast-squares technique. The slope of that line is equal to strokereserve (SR). Stroke reserve index (SRI) is equal to SR divided by BSA.

Methods for Determining Myocardial Work, Myocardial Work Index,Myocardial Work Reserve, and Myocardial Work Reserve Index

Myocardial work (M_(Y)W) comprises the work performed by the myocardiumagainst the blood in the heart during a single heart cycle. It ismathematically defined as the integral of Pressure and dV as V variesfrom V(max) to V(min) minus the integral of Pressure and dV as V variesfrom V(min) to V(max). Thus it is the work performed by the heart tissueduring systole minus the work performed on the heart tissue by the bodyduring diastole. Myocardial work may thus be expressed as the differencebetween the integral of the pressure and volume while the volume isdecreasing from the integral of the pressure and volume while the volumeis increasing: SW = ∫_(𝕕V/𝕕t < 0)P𝕕v − ∫_(𝕕V/𝕕t > 0)P𝕕vMyocardial work index (MWI) is equal to the myocardial work divided byBSA.

In some embodiments, it may also be advantageous to calculate the firstmoment of work, which could also be useful for optimization. The firstmoment of work is calculated as:SW = ∫_(𝕕V/𝕕t < 0)PV𝕕v − ∫_(𝕕V/𝕕t > 0)PV𝕕vMyocardial work index (MWI) is equal to the myocardial work divided byBSA.

In one embodiment, myocardial work reserve is calculated by firstrecording the LVEDP of a given heart cycle and then calculating themyocardial work during that cycle. This measurement may be repeated anynumber of times and multiple data pairs (LVEDP, M_(Y)W) taken. Then, anamount of fluid is injected into the left ventricle during a diastoleperiod and the resulting end-diastolic pressure recorded. The myocardialwork for that cycle is recorded using the methods described above and anew data point (LVEDP, M_(Y)W) is recorded. This process is repeated asdesired to create a set (n>=2) of data pairs. A line of regression isthen fit through the data points using a least-squares technique. Theslope of that line is equal to Myocardial reserve (M_(Y)R). Myocardialreserve index (MRI) is equal to myocardial reserve divided by BSA.

Methods for Determining Stroke Work, Stroke Work Index, Stroke WorkReserve, Stroke Work Reserve Index, and Cardiac Efficiency

Stroke work (SW) is typically defined the work performed by the leftventricle on the circulatory system. This relationship is displayed ingraphic form in FIGS. 4A and 4B. In one embodiment of the presentinvention, stroke work is determined by calculating the integral of theproduct of volume ejected into the aorta and pressure increased by theventricle. In some embodiments, the average filling pressure isdetermined and subtracted from the ventricular pressure during systole.This difference is then multiplied by the quantity of blood flowing intothe aorta. This product is then integrated over a single stroke tocalculate stroke work.${SW} = {\int_{cycle}{V_{Aorta}( {P_{systole} - \overset{\_}{P_{diastole}}} )}}$

Thus, SW is distinguishable from myocardial work. The difference betweenthese two parameters involves a difference in how regurgitant flow playsinto the measurements. Myocardial work measures the work that the heartmuscle performs, while SW measures the work the heart performs againstthe circulatory system. Cardiac efficiency (CE), yet another parameterwhich may be measured according to the present invention, is defined asthe ratio of SW over myocardial work and is a measure of the efficiencywith which the heart converts myocardial work into stroke work. Thisparameter may be used, for example, by biventricular pacing devices,pharmaceutical intervention, and other interventions to optimize theirperformance.

In an alternative embodiment, stroke work may be calculated by takingthe integral of the product of aortic pressure and aortic flow rateminus the integral of the product of left atrial pressure and flowthrough the mitral valve. With either of the two methods describedabove, the stroke work index is equal to stroke work divided by BSA. Asimilar set of calculations is possible for the right ventricle, wherestroke work would be the integral of the product of the pressure in thePulmonary Artery times the systolic volume flowing into the PulmonaryArtery minus the integral of the right atrial pressure times thediastolic volume flowing into the right ventricle.

In some embodiments, stroke work reserve is calculated by firstrecording the LVEDP of a given heart cycle and then calculating thestroke work during that cycle. This measurement may be repeated anynumber of times and multiple data pairs (LVEDP, SW) taken. Then, apredetermined amount of fluid is injected into the left ventricle duringa diastole period and the resulting end-diastolic pressure recorded. Thestroke work for that cycle is recorded using the methods described aboveand a new data point (LVEDP, SW) is recorded. This process is repeatedas desired to create a set (n>=2) of data pairs. A line of regression isthen fit through the data points using a least-squares technique. Theslope of that line is equal to stroke work reserve (SWR). Stroke workreserve index (SWRI) is equal to SWR divided by BSA.

Methods for Determining Cardiac Amplification

Cardiac amplification (CA) may be defined as the marginal increase instroke volume due to a marginal increase in end-diastolic volume. In oneembodiment, cardiac amplification is calculated by first recording theLVEDV of a given heart cycle and then calculating the stroke volumeduring that cycle. This measurement may be repeated any number of timesand multiple data pairs (LVEDV, SV) taken. Then, an amount of fluid isinjected into the left ventricle during diastole and the resultingend-diastolic volume is measured. The stroke volume for that cycle ismeasured using the methods described above and a new data point (LVEDV,SV) is recorded. This process is repeated as desired to create a set(n>=2) of data pairs. A line of regression is then fit through the datapoints using a least-squares technique. The slope of that line is equalto cardiac amplification.

Methods for Determining Valvular Gradient, Valvular Gradient Reserve,Valvular Area, Valvular Area Reserve, Valvular Regurgitation, ValvularRegurgitation Reserve, and Valvular Resistance

In one embodiment, valvular pressure gradient (VG) may be measureddirectly using two pressure sensors one upstream and the otherdownstream of a heart valve, as in the aortic valvular pressuregradient. In another embodiment, VG may be measured somewhat indirectly,as in the case of the mitral valve, where upstream pressure may bemeasured using a known pulmonary capillary wedge pressure measurementtechnique and downstream pressure is measured in the left ventricle. Ineither case, a pressure gradient across a valve may be measuredthroughout the appropriate filling period while the flow through thevalve is simultaneously determined. In the case of an aortic valve, theflow through the valve is measured using the aforementioned scaledvelocity sensor in the aorta; in the case of the mitral valve, the flowis measured as the diastolic change in ventricular volume minus anyregurgitant aortic flow measured by the scaled velocity sensor in theaorta. Throughout the filling period, multiple data pairs are recordedin the form of (ΔP, Q), where ΔP is the pressure gradient and Q is theinstantaneous volumetric flow rate through the valve. The maximumpressure gradient (ΔP) and mean pressure gradient during any cycle maythen be recorded as the VG for that cycle.

The total regurgitant flow through the valve in a cycle—valvularregurgitation (VR) may be calculated as the integral of the reversevolumetric flow rate during a cycle. In the case of aortic, pulmonic ortricuspid regurgitation, this flow may be directly determined using theoutput of the scaled velocity sensor, and is the scaled integral of allnegative volumetric flow rates during a cycle. In the case of the mitralvalve, regurgitant flow may be determined by subtracting the strokevolume (measured in the aorta using the scaled velocity sensor) from thedifference between the maximum and minimum left ventricular volumes(LVEDV−LVESV). Thus mitral regurgitant flow, in the absence of shunts,is equal to LVEDV−LVESV−SV. In some embodiments, measurement of mitralregurgitation may include factoring in any aortic regurgitation that ispresent. Since calculating stroke volume includes subtractingregurgitant (diastolic) aortic flow from the total amount of bloodejected into the aorta during a given cycle, in some embodiments theamount of aortic regurgitation is added back in to give a more accuratemeasurement of mitral regurgitation. Therefore, MR=LVEDV−LVESV−SV+AR,where MR is the net systolic mitral regurgitant flow, and AR is the net(diastolic) aortic regurgitant flow.

To calculate the effective area of a valve, one embodiment uses a knownformula (the Gorlin Formula—see Grossman's Cardiac Catheterization andAngiography, p143). Using the known formula, average flow rates such ascardiac output and mean pressure gradients are used to calculate a meanorifice area So, this embodiment uses these mean values to calculate theeffective valvular area. The equation for mean mitral valve area${({MMVA})\quad{is}\quad\frac{{CO}/( {{HR}*{DFP}} )}{( {44.3*0.85} )\sqrt{\Delta\quad P}}},$where CO is Cardiac Output in cc/min, HR is beats/min, DFP is fillingperiod in seconds/beat, and ΔP is the mean pressure gradient across themitral valve in mm Hg. This technology enables the real time estimate ofvalvular area by using instantaneous measures of flow rate and pressuregradient. Thus mitral valve area${({MVA})\quad{is}\quad\frac{Q}{( {44.3*0.85} )\sqrt{\Delta\quad P}}},$where Q is the volumetric flow rate through the valve at any point intime and ΔP is the pressure gradient at approximately the same point intime. (This pressure gradient is typically measured with the assistanceof a right heart catheter and is the difference between the pulmonarycapillary wedge pressure from the left ventricular pressure). With thisequation—modified from Gorlin and Gorlin's original—it is possible tomeasure orifice diameter as a function of time.

A similar equation is found for the aortic valve: mean aortic valve area${({MAVA})\quad{is}\quad\frac{{CO}/( {{HR}*{SEP}} )}{(44.3)\sqrt{\Delta\quad P}}},$where SEP is the Systolic Ejection Period and ΔP is this time thepressure gradient across the aortic valve. Similarly, a real timemeasurement of aortic valve area${({AVA})\quad{is}\quad\frac{Q}{(44.3)\sqrt{\Delta\quad P}}},$where Q is the instantaneous volumetric flow rate through the aorticvalve, as measured using the scaled velocity sensor in the aorta and ΔPis the pressure gradient across the aortic valve.

In one embodiment, variations in the above-described parameters(regurgitant flow, valvular area, and pressure gradient) with increasingcardiac output, are measured. One method for measuring such variationscomprises first measuring LVEDP for a given heart cycle. At thecompletion of that cycle, additional parameters related to a valve aremeasured—for example, valvular regurgitation(VR), valvular area (VA),and valvular pressure gradient (VG). Any number of these cycles may berecorded, so that multiple measurements may be averaged together. On asuccessive cardiac cycle, an amount of fluid is introduced into the leftventricle during diastole to increase end-diastolic pressure and theresultant values are again measured, typically (but not always) with ahigher cardiac output (resulting from the higher LVEDP). Multiple datasets are thus generated. To obtain the valvular gradient reserve (VGR),a least squares method is used to fit a line is fit between the multipledata pairs (LVEDP, VG). The slope of that curve is VGR. As cardiacoutput doubles, the pressure gradient should quadruple, so VGR would beexpected to increase with increasing cardiac output. It neverthelessrepresents the marginal increase in gradient with increasing LVEDPwithin the corresponding range of LVEDP.

In various embodiments, valvular area reserve (VAR) may be obtained byusing a least squares method to fit a line between the various datapairs (LVEDP, VA). The slope of that fit line is VAR, which representsthe marginal increase in valvular area due to a marginal increase inLVEDP. There are some patient populations (some disease states) wherethe effective area decreases with increasing cardiac output, and thisvalue would be negative for that class of patient.

Similarly, valvular regurgitation reserve (VRR) may be obtained by usinga least squares method to fit a line between the various data pairs(LVEDP, VR). The slope of this line is VRR, which represents themarginal increase in valvular regurgitation due to a marginal increasein LVEDP. Any of these “reserve” measurements could be made relative tocardiac output (or LVEDV, or any other variable), instead of LVEDP.

Methods for Generating Frank-Starling Curves

A Frank-Starling (F-S) curve has many definitions in the literature.They all generally relate to the change in hemodynamic output of theleft ventricle due to changes in the left ventricular end-diastolicvolume (LVEDV) or left ventricular end-diastolic pressure (LVEDP). Themost common types of F-S curves are: Cardiac Output v. LVEDP, CardiacOutput v. LVEDV, Stroke Work v. LVEDP, Stroke Work v. LVEDV, andLVESP/LVEDP v. LVEDV.

In some embodiments, an F-S curve places Cardiac Output (CO) on avertical axis and LVEDP on a horizontal axis. The catheter systemrecords the LVEDP at the beginning of one or more heart cycles and thencalculates the CO at the end of each corresponding cycle. By introducingand/or removing fluid (or increasing or reducing the volume of aninflatable balloon), the system adjusts the end-diastolic pressure to anew value and measures that value. It then calculates the resultingcardiac output for that cycle. By repeating this process over severalcardiac cycles, each using a different LVEDP as it's starting point, agraph of CO v. LVEDP is generated, recorded, and displayed to be seen bythe physician.

In other embodiments, an F-S curve that represents Cardiac Output v.LVEDV may be generated. Any of the above-described methods may be usedfor measuring CO on a per stroke basis and LVEDV on a per stroke basis.Then, by introducing and/or withdrawing amounts of fluid from theventricle during diastole, one may vary the LVEDV for one or more cyclesof the heart. If a reduced starting volume of the heart is desired, forexample to simulate a reduction in preload, a balloon may be attached tothe catheter and inflated during the systolic phase of the previousheart cycle. The balloon is then deflated during diastole to simulate areduction in preload.

Another variation of an F-S curve is to have either myocardial work(MyW) or stroke work (SW), both defined above, on the vertical axis andLVEDP on the horizontal axis. The difference between the two measures isan important indicator of valvular disease related to the leftventricle. In a manner similar to that described above for CO v. LVEDP,the system may be used simultaneously calculate MyW and SW for eachLVEDP. Cardiac efficiency (CE), the ratio of SW over MyW, may also becalculated and displayed, showing how the efficiency of the heartchanges at increasing levels of LVEDP and perhaps correspondinglyincreasing levels of cardiac output. Any of the above-describedparameters may be plotted against any other suitable parameter orparameters, as desired.

In one embodiment, to generate a CO v LVEDP curve, a real-time cardiacoutput sensor is coupled with the catheter so that it resides in theaorta. This real time sensor may be calibrated using one or more ofseveral accepted methods of measuring cardiac output, such as Fick'smethod based on oxygen consumption or the dilution method. The CO sensormay be used to measure the volume of blood ejected from the leftventricle during each cycle. At the same time, another sensor on thecatheter measures pressure inside the left ventricle. During diastole,the catheter system introduces saline or other fluid into the leftventricle and measures the resulting LVEDP. Then, as the heart completesits cycle, the CO sensor measures the output of the heart during thatcycle. The result represents a single point on the CO v LVEDP curve.After some period of time, a second point is plotted on the curve byinjecting a second bolus of saline or other liquid into the leftventricle during diastole. The cardiac output and LVEDP are thenmeasured for that cycle and the second point is plotted. Additionalpoints are generated during successive cycles and as various LVEDPconditions are created, as desired.

In another embodiment, an F-S curve based on a different definition ofstroke work is generated using a method similar to the one justdescribed. Stroke work is calculated simultaneously (or nearlysimultaneously) with cardiac output (i.e. during the same cycle). Onedefinition of stroke work which may be used is the integral of theproduct of pressure and stroke volume during a single cycle. Anotherdefinition uses the change in volume of the ventricle to determine thework performed by the heart. This latter measurement, however, includeswork required to pump regurgitant flow retrograde against the mitralvalve as well as work lost to regurgitant aortic flow. In an additionalembodiment, the stroke work is the product of the volume of bloodejected into the aorta multiplied by the pressure gradient between theventricle and the aorta. The volume of blood ejected into the aorta ismeasured by the blood velocity sensor and the pressure gradient ismeasured using the difference between two pressure sensor, one in theventricle and the other in the aorta near the velocity sensor.

As previously discussed, catheters in many embodiments of the presentinvention include means for effecting end-diastolic pressure and/orvolume by introducing and/or withdrawing an amount of fluid (such assaline, glucose, or any other suitable fluid) into or from the ventricleat a desired time during a heart cycle, such as during diastole. In oneembodiment, fluid introduction is achieved by driving an externalactuator, such as a pump, coupled with the catheter using controlsignals from the controller, such as a computer or other data processor.The timing of fluid introduction and/or withdrawal may be based uponmeasurements taken via a pressure sensor in the heart chamber. Suchmeasurements may be taken at any suitable interval, but in someembodiments they are taken at a rate of about 1000 Hz.

Methods for Generating Pressure/Volume Loops

With reference now to FIGS. 4-9, information which may be generated andoptionally displayed according to one embodiment of the invention isshown. This information is generally referred to as “pressure-volumeloops,” and such information may be displayed in various forms. In oneembodiment, a catheter is used to generate pressure-volume loops bymeasuring on a simultaneous or near-simultaneous basis intracavitarypressure and volume. The volume may be measured, for example, using sixorthogonally oriented ultrasound transducers, as described in detailabove. Referring to FIGS. 10 and 11, one embodiment of such asix-transducer device 162 on a catheter 102 is shown. As designated bythe arrows in FIG. 11, the six transducers may be used to measure sixdistances from the transducer device 162 to various locations on theinner wall of the heart chamber. These six distances represent radii ofcurvature to an inscribed ovoid. One or more phased array transducersmay alternatively be used to measure volume. In one embodiment, multiplephased array transducers have at least two arranged axially about theaxis of the catheter. In another embodiment, four phased array sensorsare arranged axially around the catheter.

Pressure may be measured using readings from one or more pressuresensors located inside the cavity (i.e., the left ventricle in FIG. 11,but any other suitable heart chamber or other cavity is contemplated).In some embodiments, the pressure sensor used in the heart chambercomprises an absolute pressure sensor, so that a pressure sensorsampling the ambient pressure is often used as well, to enable thecalculation of a gauge pressure with which most physicians are familiar.This gauge intracavitary pressure comprises the absolute intracavitarypressure minus the absolute ambient pressure. In various embodiments, anambient absolute pressure sensor may be coupled with the catheteroutside of the body or, alternatively or additionally, may be coupledwith a controller, a console, and/or the like.

Referring now to FIGS. 5A and 5B, one method of the present inventioninvolves introducing fluid (or inflating an expandable balloon) inside aheart chamber such as the left ventricle during diastole to cause ashift in a pressure/volume loop. The original loop is shown as thepoints a, b, and c, while the shifted loop (up and to the right) isshown as points a′, b′, and c′. Generally, introducing a fluid into theleft ventricle during diastole may result in a different end-diastolicpressure and/or volume, which may be measured and shown graphically as ashifted pressure/volume curve.

By introducing and/or withdrawing fluid into/from the ventricle duringdiastole, various end-diastolic pressure and volume conditions for theventricle are created. The resulting pressure and volume of theventricle may then be measured continuously as the heart completes itscycle. The integral of pressure multiplied by volume (as measured duringone heart cycle) is equal to the stroke work, as shown by the areainside the curve in FIG. 5A and on the vertical axis in FIG. 5B. Strokework as a function of end diastolic pressure is one measure ofventricular performance. Pressure/volume loops, as in FIGS. 4A and 5A,may be used to generate Frank-Starling curves, which may include any ofa number of various parameters, as described in detail above. This is avast improvement over conventional methods for generating Frank-Starlingcurves, which involve measurements taken over a period of days using aSwan-Ganz catheter to measure cardiac output, as well as administrationof one or more medications to vary the LVEDP.

Referring again to FIGS. 5A and 5B, in some embodiments of theinvention, methods may be used to calculate myocardial stiffness and/orcompliance of the heart chamber in which a catheter is positioned. Inone embodiment, a method of calculating myocardial stiffness involvesfirst measuring pressure and volume when volume is at a maximum (i.e.,at end of diastole) and then again when volume is at a minimum (i.e.,end of systole). During a subsequent heart cycle, end-diastolic pressureand volume are increased (or decreased) using one or more actuator onthe catheter, and the two sets of data points are recorded again. Anysuitable number of such pairs of data points may be measured, and theymay then be used to generate a pressure/volume curve. A least squaresroutine may then be used for each set of data pairs (i.e., theend-diastolic set and the end-systolic set) to fit a straight linebetween each set of points. The slope of the line through theend-diastolic points is the lusitropic stiffness of the heart, and theinverse of that slope is the lusitropic compliance. The slope of theline through the end systolic points is the inotropic stiffness and theinverse of that slope is the inotropic compliance. These measurementsand equations used for calculations are shown as labels on FIG. 5A.

In another embodiment, a method of measuring the compliance of a heartchamber involves continuously varying the volume in the chamber andsimultaneously measuring pressure in the chamber to give a continuousmeasure of chamber wall stiffness. In this method, a hydrophone may beused to vary the volume inside the ventricle at any suitable frequency,such as approximately 200 times per second. A pressure sensor is used tomeasure pressure change at approximately the same frequency at which itis being effected by the hydrophone. By filtering the pressure signal at200 Hz, one obtains a signal whose amplitude is proportional to thestiffness of the heart throughout the cycle. The inverse of this numberis the compliance of the heart throughout the cycle. When either valveto the ventricle is open, the method measures the effective stiffnessand compliance of the hydraulically linked chamber. Thus, when themitral valve is open, the stiffness and compliance of both the leftatria and the left ventricle, as well as some of the pulmonary vein, maybe measured. When the mitral valve is closed and the aortic valve isopen, the combined stiffness of the left ventricle and the aorta may bemeasured. When both valves are closed, as in isovolumic contraction orisovolumic relaxation, then the stiffness of the left ventricle alonemay be measured. Since the pressure/volume slope is rather steep duringeither isovolumic phase, it may be desired to use a higher frequencysuch as 1000 Hz or even 5000 Hz to measure stiffness and compliance andhow those values change during contraction or relaxation.

FIGS. 6-9 show various ways in which changes in pressure, and thusstiffness, may be displayed over a period of time. FIG. 6 shows a changein pressure when an actuator is used to effect an oscillating volumechange. FIG. 7 shows the same change, after being processed through alow-pass filter. FIG. 8 shows the same change, after being processedthrough a high-pass filter. Finally, FIG. 9 shows the same data as itrelates to systolic and diastolic stiffness of the heart chamber.

Methods for Determining Dose/Response Characteristics of Medications

In yet another embodiment, a method of the present invention may be usedto measure one or more dose/response characteristics of a medication onvarious cardiac and/or circulatory functions. Because most patients havesomewhat unique responses to a given medication, knowing thedose/response curve of any medication allows for a quantitatively basedselection among similar medications, quantitative prediction of optimaldosing levels of the chosen medication, and quantitative comparison ofthe short term effects of combinations of medications.

In one embodiment of the invention, a method involves administering anitrate-type medication to a patient in small, increasing doses, whileone or more various hemodynamic parameters and performance ratios aremonitored. Measured parameters may then be plotted on one axis of agraph, while the dose concentration of the medication is plotted on theopposing axis. For example, Cardiac Reserve (CR) (y-axis) as a functionof nitrate dose (x-axis) may be plotted. A three dimensional plot may beused to express, for example, Cardiac Reserve (z-axis) against LVEDP(x-axis) and Nitrate Dose (y-axis), where the x, y, and z axes areisometrically presented as if a corner of a cube.

In a further example, a new “set point,” or optimal hemodynamicparameter set for a patient, may be produced by some combination ofmedications at concentration levels determined during thecatheterization. (For example, the LVEDP may be lowered to some value,the cardiac output may be increased to some value, and the SVR may belowered to some value, each of which is expected to have a therapeuticbenefit.) The patient could then be given a “prescription” usingsimilar-acting oral medications to maintain that set point long afterthe catheterization has ended.

In a further example, the catheter may be placed in the aorta, where thestiffness and compliance of the aorta may be directly measured. Thistype of measurement might be used before and after a drug treatment (forexample, EDTA may be infused into the femoral vein) to test theeffectiveness of that medication in increasing aortic compliance.Similarly, the catheter may be placed in the left ventricle and thepatient given an inotropic agent whose purpose is to modify thecompliance of the ventricle. Without changing the end diastolicpressure, the effect of the medication on ventricular compliance as afunction of dosing levels may be directly measured, recorded anddisplayed.

Although the foregoing description is a complete and accuratedescription of the invention, it is offered for exemplary purposes onlyand should not be interpreted to limit the scope of the presentinvention as it is defined in the claims. Various changes, additions,substitutions, and/or the like may be made to many of the methods,devices, and systems described above, without departing from the scopeof the invention as claimed. For example, in some embodiments one ormore pharmalogical classes such as inotropic agents, phosphodiesteraseinhibitors, Beta and calcium channel blockers, diuretics, afterloadreduction agents, cardiac glycosides and neurohormonal agents may beadministered and various hemodynamic parameters may be measured. Suchmethods may be performed at rest or with exercise, with or withoutalterations in cardiac electrical stimulation, as with a pacemaker orbiventricular pacing device. Many other embodiments and variations arecontemplated within the scope of the invention.

1-78. (canceled)
 79. A system for measuring one or more parameters of aheart, the system comprising: a catheter comprising at least one sensorand at least one actuator for introducing a known volume of fluid intoat least one chamber of the heart at a selected time during a heartcycle to effect a volume change in the heart chamber; a fluid sourcecoupled with the catheter for providing fluid to the actuator; and aprocessor coupled with the catheter for processing data sensed by the atleast one sensor.
 80. A system as in claim 79, wherein the at least onesensor comprises at least one of a pressure sensor and a volume sensor.81. A system as in claim 80, wherein the at least one sensor furthercomprises at least one of a flow sensor for measuring blood flowing fromthe heart and a vascular pressure sensor for measuring pressure in avessel extending from the heart.
 82. A system as in claim 81, whereinthe at least one flow sensor or pressure sensor is disposed in alocation to measure flow or pressure in at least one of an aorta, apulmonary artery, and a coronary artery.
 83. A system as in claim 79,wherein the at least one sensor comprises at least one hydrophone.
 84. Asystem as in claim 79, wherein the at least one sensor comprises atleast one ultrasound transducer for measuring a distance within achamber of the heart.
 85. A system as in claim 84, wherein the at leastone ultrasound transducer comprises: a first pair of ultrasoundtransducers coupled with the catheter in parallel with a longitudinalaxis of the catheter for measuring a first distance between thetransducers and the wall of the chamber of the heart; a second pair ofultrasound transducers coupled with the catheter in an orientation90-degrees rotated from the first pair of transducers for measuringsecond and third distances to a wall of the heart chamber; and a thirdpair of ultrasound transducers coupled with the catheter in anorientation 90-degrees rotated from the first and second pairs oftransducers for measuring fourth and fifth distances to a wall of theheart chamber.
 86. A system as in claim 79, wherein the at least oneactuator comprises at least one of a fluid outlet port and an expandableballoon, the expandable balloon being expandable by introducing thefluid into the balloon.
 87. A system as in claim 79, further comprisingan electrocardiogram device coupled with the processor for measuring theheart cycle.
 88. The system as in claim 79, wherein said system isconfigured to cause a change in at least one of volume and pressure in aheart chamber at a selected time during a heart cycle; measure a changein at least one characteristic of the heart chamber which occurs inresponse to the change in at least one of volume and pressure; andcalculate at least one cardiac performance parameter based on a ratio ofthe measured change in the characteristic to the caused change.
 89. Thesystem as in claim 88, wherein said system is configured to repeat thecausing a change, measuring and calculating steps over a series of twoor more consecutive heart cycles.
 90. The system as in claim 88, whereinsaid system is configured to measure a change in at least one pressurewithin the heart chamber.
 91. The system as in claim 88, wherein saidsystem is configured to measure a change in at least one volume withinthe heart chamber.
 92. The system as in claim 88, wherein said system isconfigured to measure a change in at least one pressure and a change inat least one volume within the heart chamber.
 93. The system as in claim88, wherein said system is configured to measure a change in at leastone flow rate of blood flowing out of the heart chamber which occurs inresponse to the volume and/or pressure change; and calculate at leastone flow-related parameter of the heart chamber based on a ratio of themeasured change in the flow rate to the volume and/or pressure change.